Methods: Two weeks of CIMT was delivered to participants immediately after randomization early group or 1 year later delayed group. Evaluators blinded to group designation administered primary Wolf Motor Function Test, Motor Activity Log and secondary Stroke Impact Scale outcome measures among the early participants and 86 delayed participants before delivery of CIMT, 2 weeks thereafter, and 4, 8, and 12 months later.
Early and delayed group comparison of scores on these measures 24 months after enrollment showed no statistically significant differences between groups. Improvements mean less time to complete tasks or greater strength in the two force tasks. The timed tasks are arranged progressively to engage more upper extremity joints. The WMFT was administered at all 9 clinical assessment points.
Each WMFT task is also assessed by masked raters from video records on a 6—point Functional Ability Scale FAS for quality of movement before and after the intervention and twice at two week intervals after one year. Assessment is done on a 6-point scale. The MAL was administered to participants and available caregivers independently. Participants were evaluated at all 9 clinical assessment points.
The SIS, a full-spectrum health status and quality of life assessment, was administered at baseline and at months 4, 12, 16 and This interview instrument measures changes in 8 impairment, function, and quality of life domains following stroke, plus an overall measure of physical function.
Key moderators were examined to determine the extent to which they mediated outcome measures over time. These variables included functional level, gender, and concordance of stroke. Functional level is defined above in Patients and Participants. Concordance of stroke is defined as either concordant dominant hand is also stroke-affected hand or discordant dominant hand is not stroke-affected.
This paper examined data from participants randomized within days of enrollment to receive CIMT immediately and followed their outcomes through 24 months to determine the extent to which improvements in primary outcome measures one year after CIMT 15 were retained through the 24 month endpoint. Dependencies between values measured at different times were modeled with an AR 1 covariance structure. Significance of the difference is done by repeated measures F test.
Directionality of the difference, if significant, will be indicated by looking at relevant columns in Table 1. Retention means that either no change maintaining the improvement post-training or a significant further improvement between M12 and M24 occurred.
A decrease in function from M12 to M24 meant there was no retention. WMFT-T was analyzed both untransformed and with a log transformation to reduce skewness.
The granting agency for this study had no role in study design, data collection, analyses or interpretation, or in the writing of this report. The corresponding author had full access to all the data in this study as well as responsibility for the decision to submit for publication. The consort diagram Figure 1 shows patient flow through the two years of the EXCITE program for those individuals receiving CIMT immediately and one year after enrollment delayed and reasons for withdrawal from the trial.
These rates were For the WMFT time values and the MAL items, the treatment effect observed at 12 months was not eroded; moreover, the average change was in the direction of an additional treatment effect.
For the SIS domains, all 5 of the presented scales show continued improvement. In general, results for each of the moderating factors in Table 2 were similar to those of the entire group.
Differences are detailed below. For the High Functioning participants, SIS scales show significant differences in the Retain terms, and this observation is due to continued improvement among these individuals. For non-dominant hand paresis Discordant and for dominant hand paresis Concordant , improvement is seen for all variables except SIS Physical Problems and Memory Thinking domains.
While the number of randomized clinical trials in stroke neurorehabilitation is growing, to date none of them has documented the retention of CIMT past one year. Therefore, the present findings extend previous observations by showing that the improvements in function noted at 12 months following a 2-week CIMT intervention are retained or improve even further WMFT strength tasks, SIS domains 1,2,5, 8 and physical domain. Collectively these observations highlight the possibility of further improvements in the upper extremities of mild to moderately impaired stroke survivors beyond one year following a 2-week CIMT intervention.
Grip strength improved over 24 months among all participants irrespective of concordance or gender. The weight-to-box WTB UE strength task improved in higher functioning participants without respect to concordance or gender and these improvements were retained.
WTB strength is specific for shoulder musculature. The literature on strength changes in hemiparetic upper extremity muscles is equivocal with indications that while improved strength is possible, 29 the functional ramifications of such changes are uncertain.
During the first 12 months, higher and lower functioning patients receiving CIMT did not have significantly different treatment effects. Such differences might be manifest in the potential for cortical plasticity to be more profound among higher functioning patients, a notion that is supported by enlarged cortical representation following CIMT in higher functioning, chronic stroke survivors.
MAL scores that had improved following CIMT showed consistency throughout the following year and hovered about a mean score of 2. This observation complements findings by Dettmers et al 33 who reported initial changes in hand function after distributed CIMT with subsequent improvement in social participation, measured by the SIS. The relationship between dexterity Hand Function , strength and overall function is complex.
Strength and dexterity contribute to improved function 34 , 35 and activities of daily living 36 ; yet, upper extremity function, and not strength or dexterity independently, seems to have the strongest link to health related quality of life or participation. This possibility is particularly important, because gains in participation reflect active engagement in activities for one's overall well being.
The inter-relationships of strength, dexterity, and function are even more convoluted when moderating factors concordance, gender are examined. In a sub-study of EXCITE participants that evaluated factors impacting quality of life, concordance affected overall quality of life across the SIS domains at baseline. Male gender has also been previously reported to have a three fold impact on recovery of ADL skills, which was thought to be associated with the greater strength levels in men or the increased willingness of women to solicit help.
The fact that memory-thinking domain of the SIS did not change after administration of CIMT is consistent with observations made by Dettmers et al 33 who applied the same amount of CIMT over a longer time period and at a six month follow up.
The lack of change in this domain is not surprising given that CIMT does not target cognitive function. In general, our stroke survivors achieved a higher quality of life that persisted over time, which is an ultimate goal of rehabilitation. In conclusion, we found that the improvements in functional gains following the provision of a standardized 2-week CIMT program that were still present at 12 months were retained for an additional year. Significant differences post-training indicate continued improvement over that period.
Specific gains in upper extremity strength improved further during the second year. These results emphasize the importance of long-term follow-up in rehabilitation clinical trials to determine more adequately the full extent of effects from therapeutic interventions.
Wolf, Ph. University of Alabama at Birmingham. Louis and is directed by J. Philip Miller. We wish to thank our project coordinators, evaluators and trainers at all the EXCITE locations for their tireless and dedicated efforts throughout this trial.
SLW made primary contributions to the drafting and approval of the final manuscript as well as to the conceptualization and rationale of the study and interpretation of the study. ET made primary contributions to the conceptualization and rationale of the study as well as drafting and approval of the manuscript. JPM and PT made primary contributions to data analyses and drafting of the manuscript. Conflict of interest statement : We have no conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Steven L. Carolee J. F values omitted to simplify table. Differences post-training between values at time points were assessed between groups.
These tests were not significant, indicating that only minor differences between groups occurred after training results not shown. Tests comparing results for time points separately for each group were not significant using Bonferonni-corrected tests results not shown. There were no differences in patient demographics between groups when they were initially randomized. Table 2 presents the least squares means for all primary and secondary outcome measures for the time points relative to the year of intervention.
This test compares the results 12 months post-baseline between groups while adjusting for the pre-training level. A subsequent analysis that examines differences between the groups 24 months after enrollment Table 1 , column 3 indicates no significant differences on the WMFT and both MAL measures.
No demographic or baseline characteristics predicted study withdrawal during the year following treatment. Withdrawal post-treatment was examined using logistic regression and for time to event Cox regression.
Using Bonferroni-corrected p-values, no predictor was significant for either method. For three important variables gender, concordance, and functional ability , the 3-way interactions between treatment, evaluation and covariate were examined for outcome variables. Severe adverse events SAEs occurring during the first year were presented previously. During the Pre 2 to 24 month interval, D-CIMT participants sustained one death and 10 individual SAE hospitalizations emphysema, internal bleeding, second stroke, cancer, congestive heart failure, subdural hematoma, hypertension, chest pain, hip arthroplasty, two fractures.
None of those events was related to the intervention. Until now, there has been little to no level I evidence to inform the hypothesis that earlier CIMT is better than later.
Indeed, evidence from other animal 13 and human 14 stroke studies suggest that limb rehabilitation within days of a stroke may be detrimental to recovery. Some studies indicate CIMT delivered to chronic stroke survivors resulted in far more substantial improvements than those seen in acute patients. While both groups improved, those participants receiving treatment within 3—9 months post-stroke demonstrated significantly greater changes from immediately before to 12 months after treatment.
This finding supports other studies showing that rehabilitation applied sooner during the recovery phase results in a faster rate of change; 16 however, increasing CIMT from 2 to 3 hours per day applied within a few days after stroke does not necessarily produce superior outcomes. To date, structural reorganization associated with early training has been characterized by maintenance of the original focus of motor control primary motor cortex ; while training in the chronic phase was characterized by increases in bilateral sensory-motor, premotor and hippocampal activity Recovery in the chronic state may be influenced by the loss of hand and expansion of non-hand representation areas within the primary motor cortex during the delayed period that contribute to atypical movement patterns and compete with subsequent neural reorganization during later training periods 24 , resulting in smaller treatment effects in the chronic versus the acute periods 25 as seen in this study.
Similar to findings from our first year analyses, 5 these chronicity effects were not affected by functional level amount of active wrist and finger range of motion , concordance or gender. The most apparent and likely biggest factor for the greater treatment effect in early vs. The possibility that the quarterly evaluation visits alone may have focused attention on paretic limb use during the no-training interval cannot be ruled out. The magnitude by which this chronic group could improve after CIMT might well have been limited by: the extent of which they could improve or the extent to which our outcome measures were sensitive to improvements resulting from continued efforts to use the limb during the post-enrollment interval; changes in motivation; limitations in motor control caused by persistence or changes in muscle tone or strength; alterations in self-perception of the potential for limb use; 26 or neuroplastic reorganization of the sort mentioned earlier.
Therefore, while one can conclude from the data that CIMT produces improvement in motor measures that are greater when administered 3 to 9 months after stroke compared to one year later, our data also suggest that comparable results for both groups may occur after the full period of training and evaluation. In fact, both groups demonstrated significant gains at the end of their respective 10 sessions CIMT and then maintain these gains throughout the subsequent year.
In addition to uncertainties about the optimal delivery 28 and intensity of CIMT training 29 , 30 , alternative forms of delivery using distributed rather than intense blocked practice models need to be explored. For example, small scale studies by Page 31 and Wu 32 offer the potential for comparable results with less intense individualized training. However, the optimal modification of CIMT needs to be defined first followed by a direct comparison to the present mode using a large enough sample size to undergo the rigors of an intention-to-treat analysis.
The results from this study show that the improvements persist, and none of the severe adverse events were related to CIMT. National Center for Biotechnology Information , U.
Author manuscript; available in PMC Oct 1. Steven L. Wolf , Ph. Thompson , Ph. Winstein , Ph. Phillip Miller , A. Blanton , D. Nichols-Larsen , Ph. Morris , Ph. Light , Ph. Author information Copyright and License information Disclaimer. Department of Rehabilitation Medicine S.
Corresponding Author: Steven L. Wolf, PH. Copyright notice. The publisher's final edited version of this article is available at Stroke. See other articles in PMC that cite the published article.
Abstract Background and Purpose Although constraint-induced movement therapy CIMT has been shown to improve upper extremity function in stroke survivors at both early and late stages post-stroke, the comparison between participants within the same cohort but receiving the intervention at different time points has not been undertaken. Methods Two weeks of CIMT was delivered to participants immediately after randomization early group or one year later delayed group.
Conclusions CIMT can be delivered to eligible patients 3 to 9 months or 15 to 21 months following stroke.
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